Schizophrenia has been considered a neurodevelopmental disorder for over two decades, yet the specific neurodevelopmental mechanisms that contribute to the cortical pathology central to schizophrenia remain unknown. Genetic vulnerability for schizophrenia has been recognized for almost 100 years;nevertheless, the relationship between genetic risk and specific neurodevelopmental mechanisms is unclear. The UNC Conte Center, "Prospective Studies of the Pathogenesis of Schizophrenia," will answer three key questions in an effort to synthesize neurodevelopmental mechanisms, genetic vulnerability, and the development of schizophrenia: 1) At what stage of development does cortical pathology arise in children at risk for schizophrenia? 2) How does cortical pathology contribute to the developmental expression of cognitive deficits and clinical symptoms of schizophrenia? and 3) Can an apparently diverse set of developmental mechanisms and risk genes give rise to a common cortical pathology implicated in schizophrenia? The central hypothesis of this competitive renewal of the UNC Conte Center is that genetic vulnerability for schizophrenia can compromise multiple mechanisms of early cortical development, each of which can ultimately contribute to aberrant cortical circuitry, neurocognitive deficits, and the clinical symptoms of schizophrenia. The clinical projects of the UNC Conte Center will use state-of-the-art multimodal imaging and image analysis to study the development of cortical structure and function in children at genetic high risk for schizophrenia during the two critical periods of cortical synaptic development: synaptic elaboration during early childhood (Project 1), and synaptic remodeling and elimination during adolescence (Project 2). In parallel, the preclinical projects will assess cortical precursor proliferation, neuronal migration and synapse formation in mouse models of three well characterized sets of risk genes: NCAM (Project 3);22q11 genes (Project 4), and Neuregulin/Erb4 (Project 5). These projects will be supported by 3 cores - 1) Administrative, 2) Neuroimage Analysis 3) Biostatistics and Data Management;each part of the current Conte Center. Our goal is to synthesize clinical characterization of abnormal cortical structure and function in genetically vulnerable children with detailed assessment of abnormal neurodevelopmental mechanisms in the cortex of mice carrying mutations in specific risk genes. UNC Conte Center offers a focused, directed, and integrated set of clinical and basic projects and experiments that will identify fundamental mechanisms of cortical development that are the basis of the neurodevelopmental pathogenesis that is thought to underlie schizophrenia.